Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1α PARylation in db/db mice

Abstract

Objective Human TNKS, encoding tankyrase 1 (TNKS1), localizes to a susceptibility locus for obesity and type 2 diabetes mellitus (T2DM). Here, we addressed the therapeutic potential of G007-LK, a TNKS-specific inhibitor, for obesity and T2DM. Methods We administered G007-LK to diabetic db/db mice and measured the impact on body weight, abdominal adiposity, and serum metabolites. Muscle, liver, and white adipose tissues were analyzed by quantitative RT-PCR and western blotting to determine TNKS inhibition, lipolysis, beiging, adiponectin level, mitochondrial oxidative metabolism and mass, and gluconeogenesis. Protein interaction and PARylation analyses were carried out by immunoprecipitation, pull-down and in situ proximity ligation assays. Results TNKS inhibition reduced body weight gain, abdominal fat content, serum cholesterol levels, steatosis, and proteins associated with lipolysis in diabetic db/db mice. We discovered that TNKS associates with PGC-1α and that TNKS inhibition attenuates PARylation of PGC-1α, contributing to increased PGC-1α level in WAT and muscle in db/db mice. PGC-1α upregulation apparently modulated transcriptional reprogramming to increase mitochondrial mass and fatty acid oxidative metabolism in muscle, beiging of WAT, and raised circulating adiponectin level in db/db mice. This was in sharp contrast to the liver, where TNKS inhibition in db/db mice had no effect on PGC-1α expression, lipid metabolism, or gluconeogenesis. Conclusion Our study unravels a novel molecular mechanism whereby pharmacological inhibition of TNKS in obesity and diabetes enhances oxidative metabolism and ameliorates lipid disorder. This happens via tissue-specific PGC-1α-driven transcriptional reprogramming in muscle and WAT, without affecting liver. This highlights inhibition of TNKS as a potential pharmacotherapy for obesity and T2DM.

Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines

“…However, among upregulated proteins, the energy metabolism-regulating proteins transketolase, NADH:ubiquinone oxidoreductase subunit A8, and hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta were identified in a minimum of four of the cell lines after G007-LK treatment (Table S4). Previous reports have shown TNKSi-mediated regulation of energy metabolism in mouse models (Wang et al, 2020;Zhong et al, 2016aZhong et al, , 2016b.…”

“…TNKS1/2 can orchestrate the activities of several biological mechanisms including proliferation, differentiation, energy metabolism, vesicle transport, telomere homeostasis, and mitotic spindle formation through a multitude of direct poly-ADP-ribosylation targets (Haikarainen et al, 2014;Kim, 2018;Wang et al, 2020;Zimmerlin and Zambidis, 2020). Importantly, TNKSi has been reported to inhibit key cancer-promoting signaling pathways (Sanchez-Vega et al, 2018), such as the wingless-type mammary tumor virus integration site (WNT)/b-catenin pathway (Huang et al, 2009), the yes-associated protein 1 (YAP) pathway (Wang et al, 2015), the PI3K/AKT serine/threonine kinase 1 (AKT) pathway (Li et al, 2015), and the notch receptor (NOTCH) pathway (Bhardwaj et al, 2017).…”

Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

“… 5 − 8 TNKS1/2 PARylate a plethora of target proteins including peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α), telomeric repeat binding factor 1 (TRF1), phosphatase and tensin homologue (PTEN), AMP-activated protein kinase (AMPK), SRY-box transcription factor 9 (SOX9), and SH3 domain binding protein 2 (SH3BP2). 3 , 9 − 15 In particular, TNKS1/2 regulate the turnover of AXIN1, AXIN2 (AXIN1/2) and of angiomotin (AMOT) proteins at the crossroad of the elementary wingless-type mammary tumor virus integration site (WNT)/β-catenin and Hippo signaling pathways, respectively. 3 , 14 , 16 , 17 Hence, controlling the catalytic activity of tankyrase by pharmacological intervention provides an attractive tool for reducing WNT/β-catenin and Hippo signaling.…”

Pleiotropic role of PARP1: an overview

“…Inhibition of PARP1 reduces the total serum cholesterol levels. It improves the ratio of the high-density lipoprotein to low-density lipoprotein (HDL/ LDL ratio), thus showing beneficial effects in conditions such as high-fat feeding or high cholesterol feeding and diabetes (Hans et al 2009;Wang et al 2020).…”